Table 4. Summary of absorption, distribution, metabolism and elimination of AR.
| Model | Dose | Findings | Ref |
|---|---|---|---|
| Absorption | |||
| Caco-2 cell monolayer | 50 μg/mL | AR efficiently passed through the cell monolayer with Papp of (1.76±0.48)×10−5 (apical to basolateral) and (1.50±0.61)×10−5 (basolateral to apical). | 68 |
| In situ SD rat intestinal perfusion model | 25 μg/mL | Efficient absorption of AR was observed with extensive intestinal first-pass metabolism demonstrated. | 68 |
| In situ intestinal perfusion on normal and diabetic SD rats | 5, 10, 20 μg/mL | AR belongs to easily absorbed agents. Duodenum was the best absorption segment of AR. The Peff and Ka of AR were increased by 60% and 52% in duodenum with co-treatment of verapamil. The absorption of AR was promoted in diabetic rats. | 67 |
| Distribution | |||
| In vitro plasma incubation | 0.0672, 0.269, 1.075 μmol/L | R exhibited a strong binding capacity (99.8%–100%) with plasma, including human, beagle dog, and rat. | 69 |
| Wistar rat | 0.806 μmol/kg, ih | AR concentration in the intestine was the highest, followed by heart, liver, pancreas, and kidney. No accumulation of AR in tissues after 6 h. | 69 |
| SD rat | 30, 50, 70 mg/kg, po | AR was rapidly distributed into organs, and Cmax in tissues was observed at 30 min. The content of AR in spleen was the highest. | 70 |
| Metabolism and elimination | |||
| Human fecal inoculum incubation | 0.2 to 0.35 mmol/L | Three metabolites of AR were identified under anaerobic condition: enterolactone (3), 3′-demethyl-4′-dehydroxyarctigenin and 3′-demethylarctigenin. | 65 |
| Eubacterium ARC-2 incubation | 0.6 mmol/L | After 24-h incubation, AR was transformed to 4′, 4′-dihydroxylenterolatone through 3 types of demethylation products under anaerobic condition. | 61,71 |
| Rat intestinal content solution | After 4-h incubation, AR was stable in rat small and large intestinal content solution, while arctigenic acid was converted back to arctigenin in rat large intestinal content. All three glucuronides, were hydrolysed back to corresponding parent compounds. | 72 | |
| In situ SD rat intestinal perfusion model | 25 μg/mL | Extensive intestinal first-pass metabolism of AR to arctigenic acid (4) and arctigenin-4′-O-glucuronide (5) was identified. | 68 |
| Human recombinant paraoxonase 1 | 0.27 to 134.4 μmol/L | Paraoxonase 1 was confirmed to be the enzyme responsible for AR hydrolysis. | 73 |
| V79 Chinese hamster cells with rat Cyp2b1 | 1 mmol/L | AR was converted to 3′-demethyl-arctigenin in cells expressing rat Cyp2b1. | 125 |
| Rat liver/intestine microsome | 0.269 to 67.2 μmol/L | Extensive glucuronidation of AR was observed in both liver and intestine microsome. No further glucuronidation or demethylation of arctigenic acid (4) in liver and intestine microsome. | 72 |
| Rat liver cytosol incubation | 10 nmol/L | 3′-Demethyl-arctigenin was converted back to AR. | 126 |
| Human liver/intestine microsomes | 100 μmol/L | AR was metabolized to 4'-O-glucuronide (5) in human liver and intestinal microsome mainly via UGT1A9, UGT2B7 and UGT2B17. | 74 |
| Human, monkey, dog, and rat liver microsome | 100 μmol/L | Around 62%, 3.7%, 25.9% and 15.7% of AR remained after incubated in human, monkey, dog, and rat liver microsome for 90 min. | 69 |
| SD rats | 3 mg/kg, po | Arctigenic acid (4) and arctigenin-4′-O-glucuronide (5) was identified as major metabolites in rat plasma after oral administration of AR. 4-O-demethylarctigenin was also identified in vivo. | 73 |
| SD rats | 0.48 to 2.4 mg/kg, iv; 2.4 to 12 mg/kg, po | Rapid formation of arctigenic acid (4) and arctigenin-4′-O-glucuronide (5) with quick elimination of both parent and metabolites were observed after both intravenous and oral administrations. No quantifiable AR was identified after oral administration due to extensive first-pass metabolism | 72 |
| SD rats | 0.96 mg/kg, iv | Arctigenin-4′-O-glucuronide (5), arctigenic acid-4′-O-glucuronide, 4-O-demethyl-arctigenin -4,4′-O-di-glucuronide, and trace amount of arctigenic acid (4) were found in bile at 0–15 min. | 72 |
| Wistar rat | 0.806 μmol/kg ih | Within 72 h after drug-delivery, the urine accumulative excretion ratio was 1.93% and the excretory amount of AR in faeces and bile were 0.248% and 0.182%, respectively. | 69 |
Abbreviation: iv: intravenous administration; ih: hypodermic injection; po: oral administration.